Differential modulation of RANKL isoforms by human osteoarthritic subchondral bone osteoblasts: Influence of osteotropic factors

Abstract

Background-Osteoarthritis (OA) is the most common human joint disease. Recent studies suggest that an abnormal subchondral bone metabolism is intimately involved in the genesis of this disease. Bone remodelling is tightly regulated by a molecular triad composed of OPG/RANK/ RANKL. RANKL exists as 3 isoforms: RANKL1, 2, and 3. RANKL1 and 2 enhance osteoclastogenesis whereas RANKL3 inhibits this phenomenon. We previously reported that human OA subchondral bone osteoblasts can be discriminated into two subgroups according to their level of PGE 2 [low (L) or high (H)]. Moreover, we also showed that L-OA osteoblasts express higher levels of total RANKL compared to H-OA osteoblasts. In this study, we investigated the level of membranous RANKL, comparing L-and H-OA subchondral bone osteoblasts, as well as its modulation by osteotropic factors. The impact of the modulation of RANKL1 and 3 on the membranous RANKL level was also studied.

Local origins impart conserved bone type-related differences in human osteoblast behaviour

“…Cells derived by outgrowth or by enzyme digestion are heterogeneous, consisting predominantly of early osteoblasts that show accelerated maturation (with matrix formation, mineralisation and osteogenic markers) in response to exogenous glucocorticoids, vitamin D or bone morphogenic proteins Beresford et al, 1993;Declercq et al, 2004;Lian and Stein, 1995;Liu et al, 1994;Liu et al, 1997;Siggelkow et al, 1999;Wong et al, 1990). Attainment of osteoblast confluence is significantly slower from the aged and diseased human bone samples used herein, than in other systems (Czekanska et al, 2012;Perinpanayagam et al, 2001;Siggelkow et al, 1999), yet is nonetheless comparable with outgrowth kinetics described previously in similar aged human bone samples (Couchourel et al, 2009;Couchourel D and Delalandre A, 2008;Hilal et al, 1998;Hilal et al, 2001;Massicotte et al, 2002;Tat et al, 2008). It is therefore striking and somewhat discordant with popular dogma (Dodds et al, 1989;Dodds et al, 1990;Varanasi et al, 2010) that we find initial osteoblast explant outgrowth to be slower in trabecular than in subchondral or cortical type bone.…”

“…This is perhaps accentuated by studies distinguishing two separate groups of subchondral bone OA osteoblasts: 'low' -which resemble normal osteoblasts -and 'high' osteoblasts with corresponding prostaglandin E 2 and IL-6 levels (Hilal et al, 2001;Massicotte et al, 2002). More recent data indicate a close relationship between these OA subchondral osteoblasts and the OPG/RANK/ RANKL system, linking to structural bone changes in OA (Tat et al, 2008;Tat et al, 2009). It was found that 'low' osteoblasts express depleted TNFRSF11B, but high TNFSF11 levels, whereas 'high' OA osteoblasts express the reverse (Tat et al, 2008).…”

“…More recent data indicate a close relationship between these OA subchondral osteoblasts and the OPG/RANK/ RANKL system, linking to structural bone changes in OA (Tat et al, 2008;Tat et al, 2009). It was found that 'low' osteoblasts express depleted TNFRSF11B, but high TNFSF11 levels, whereas 'high' OA osteoblasts express the reverse (Tat et al, 2008). Consideration of these findings in the light of our own, which shows that trabecular type osteoblasts express lower TNFRSF11B:TNFSF11 ratios compared to subchondral and cortical osteoblasts, implies that 'low' -more normal -subchondral osteoblasts show greater resemblance with those derived from trabecular compartments.…”

New Perspective in Osteoarthritis: The OPG and RANKL System as a Potential Therapeutic Target?

“…[67][68][69][70][71] In situ histological examination of the subchondral bone revealed that the thickness of this tissue was reduced in the L-OA and increased in the H-OA patients compared to normal individuals. 70 Further experiments in which the bone remodelling factors OPG and RANKL were determined in OA subchondral bone osteoblasts compared to normal revealed that in both the L-OA (having low endogenous levels of PGE 2 ) and H-OA (having high endogenous levels of PGE 2 ) osteoblasts, OPG and RANKL were abnormally expressed and consequently the OPG/RANKL ratio was reduced in the L-OA, suggesting increased subchondral bone resorption, and increased in H-OA, indicating a shift toward bone formation.…”

The balance between soluble receptors regulating IL-6 trans-signaling is predictive for the RANKL/osteoprotegerin ratio in postmenopausal women with rheumatoid arthritis

“…On the other hand, through suppression of proinXammatory cytokines GC can indirectly downregulate RANKL expression resulting in potential protective eVects on bone in the setting of active inXammation. Calcium-regulating hormones such as parathyroid hormone (PTH) and calcitriol (1,25[OH] 2 D 3 ) can stimulate RANKL expression [8]. On the other hand, the synthesis and secretion of 1,25(OH) 2 D 3 and PTH are inXuenced itself by the inXammatory process in RA [11].…”